Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound, comprising an amide of the formula 
wherein R1 and R2 are independently hydrogen, halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R3 is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R4 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl; 
R5 and R6 are hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
The compounds of formula I have been found to activate glucokinase in vitro. Glucokinase activators are useful in the treatment of type II diabetes.
This invention provides a compound, comprising an amide of the formula 
wherein R1 and R2 are independently hydrogen, halo, amino, nitro, cyano, sulfonamido, lower alkyl, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl; R3 is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R4 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, 
R5 and R6 are hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. In preferred compounds, the amide is in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown.
In certain compounds of this invention, R4 of the amide is hydrogen, lower alkyl, or lower alkenyl. Such amides are preferred when R3 is cyclopentyl, especially when the amide is in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown.
In certain amides of the above compound, R1 and R2 of the amide are hydrogen. Such an amide is 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea. In other of the above compounds, one of R1 and R2 is hydrogen and the other is cyano or halo.
Examples of Such Amides Are
1-[2-(3-chloro-phenyl)-3cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl urea.
In other amides of the above compound, R1 and R2 of the amide are each independently halo (preferably chloro). Examples of such amides are [3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea;
1-[3-cyclopentyl-2R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea;
1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea;
1-allyl-3-[3-cyclopentyl-2R)-(3,4-dichloro-phenyl)-proprionyl]-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea;
1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-isopropyl-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-propyl-urea;
1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-methyl-urea.
In yet other amides of the above compound, one of R1 and R2 of the amide is hydrogen or halo and the other is nitro. Examples of such amides are
1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea.
1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]-3-methyl-urea.
In further amides of the above compound, one of R1 and R2 is hydrogen, lower alkyl thio or perfluoro-lower alkyl thio and the other is lower alkyl thio or perfluoro-lower alkyl thio. Examples of such amides are
1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea;
1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea.
In yet further amides of the above compound, one of R1 and R2 is hydrogen or perfluoro-lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl. Examples of such amides are
1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea;
1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea.
In certain amides of the above compound, at least one of R1 and R2 is lower alkyl sulfonyl. Preferably one of R1 and R2 is hydrogen or lower alkyl sulfonyl and the other is lower alkyl sulfonyl, and more preferably R2 is lower alkyl sulfonyl. Examples of such amides are
1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea;
1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-proprionyl}-3-methyl-urea;
1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-proprionyl]-3-methyl-urea;
1-[2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea.
In other amides of the above compound, at least one of R1 and R2 is lower alkyl sulfonyl, one of R1 and R2 is cyano or halo and the other, preferably R2, is lower alkyl sulfonyl. Examples of such amides are
1-[2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea;
1-[3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-proprionyl]-3-methyl-urea;
1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea;
1-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea;
1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-ethyl-urea;
1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-proprionyl]-3-methyl-urea.
In other amides of the above compound, at least one of R1 and R2 is lower alkyl sulfonyl, one of R1 and R2 is perfluoro-lower alkyl and the other, preferably R2, is lower alkyl sulfonyl. Examples of such amides are 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-proprionyl]-3-methyl-urea.
In further amides of the above compound, at least one of R1 and R2 is perfluoro-lower alkyl and the other is halo. Examples of such amides are
1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl]-3-methyl urea;
1-[3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionyl]-3-methyl urea.
In yet further amides of the above compound, at least one of R1 and R2 is lower alkyl sulfonyl, one of R1 and R2 is nitro and the other is lower alkyl sulfonyl. An example of such an amide is 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3-methyl-urea.
In the compounds of this invention described above, R4 of the amide is hydrogen, lower alkyl, or lower alkenyl and R3 is cyclopentyl. In the compounds described below, R4 is the same but R3 is not cyclopentyl.
In certain such compounds, one of R1 and R2 is halo or hydrogen and the other is hydrogen,. An example of such an amide is [2-(4-chloro-phenyl)-4-methyl-pentanoyl]-urea. In particular R1 and R2 may each be chlorine. Examples of such amides are
[3-cyclopropyl-2-(3,4-dichloro-phenyl)-propionyl]-urea;
[3-cyclobutyl-2-(3,4-dichloro-phenyl)-propionyl]-urea;
R-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-urea;
1-[2-(3,4-dichloro-phenyl)-4-methyl-pentanoyl]-3-methyl-urea;
1-[2-(3,4-dichloro-phenyl)-hexanoyl]-3-methyl-urea.
In other such compounds, R4 is as described above and R3 is cyclohexyl. In some such amides, one of R1 and R2 is halo or hydrogen and the other is halo. Examples of such amides are
3-[cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-urea;
[3-cyclohexyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea.
In other such compounds, R4 is as described above and R3 is cycloheptyl. In some such amides, one of R1 and R2 is halo or hydrogen and the other is halo. An example of such an amide is [3-cycloheptyl-2-(3,4-dichloro-phenyl)-propionyl]-urea.
In certain compounds of this invention, R4 is 
In some such compounds, R3 of the amide is cyclopentyl. Preferably R1 and R2 are independently halo.
Examples of the Above Amides Are
3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid ethyl ester;
{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid ethyl ester;
{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid methyl ester;
3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid methyl ester;
{3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid ethyl ester;
3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-3-oxo-propionic acid ethyl ester.
In certain compounds of this invention, R4 is hydroxy lower alkyl, or halo lower alkyl. In some such compounds, R3 of the amide is cyclopentyl. Preferably R1 and R2 are independently halo, and in addition the amide is in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown.
Examples of the Above Amides Are
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-ethyl)-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(2-hydroxy-propyl)-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea;
1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-(2-hydroxy-propyl)-urea;
1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-proprionyl]-urea;
1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-proprionyl]-3-(3-hydroxy-propyl)-urea.
In the compound of formula I, the * indicates the asymmetric carbon. The compound of formula I may be present either as a racemate or in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown. The xe2x80x9cRxe2x80x9d enantiomers are preferred.
As used herein, the term xe2x80x9chalogenxe2x80x9d and the term xe2x80x9chaloxe2x80x9d, unless otherwise stated, designate all four halogens, i.e. fluorine, chlorine, bromine and iodine. A preferred halogen is chlorine
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. With regard to R3, isopropyl and n-propyl are preferred. xe2x80x9cHalo lower alkylxe2x80x9d as used herein designates a lower alkyl group wherein one of the hydrogens is replaced by a halogen as defined above, which replacement can be at any site on the lower alkyl, including the end. A preferred halo lower alkyl group is chloroethyl. Similarly, xe2x80x9chydroxy lower alkylxe2x80x9d designates a lower alkyl group where one of the hydrogens is replaced by a hydroxy, at any site including the end. Preferred hydroxy lower alkyl groups include ethanol, isopropanol, and n-propanol. As used herein, xe2x80x9cperfluoro-lower alkylxe2x80x9d means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
As used herein, xe2x80x9clower alkyl thioxe2x80x9d means a lower alkyl group as defined above where a thio group is bound to the rest of the molecule. Similarly xe2x80x9cperfluoro-lower alkylxe2x80x9d thio means a perfluoro-lower alkyl group as defined above where a thio group is bound to the rest of the molecule.
As used herein, xe2x80x9clower alkyl sulfonylxe2x80x9d means a lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule. Similarly xe2x80x9cperfluoro-lower alkyl sulfonylxe2x80x9d means a perfluoro-lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule.
As used herein, xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A preferred cycloalkyl is cyclopentyl.
As used herein, the term xe2x80x9clower alkenylxe2x80x9d denotes an alkylene group having from 2 to 6 carbon atoms with a double bond located between any two adjacent carbons of the group. Preferred lower alkenyl groups are allyl and crotyl.
As used herein, the term xe2x80x9clower alkoxyxe2x80x9d includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy.
During the course of the reaction the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term xe2x80x9chydrolyzable ester or ether protecting groupsxe2x80x9d designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxcyclic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxcyclic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or xcex1-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
The term xe2x80x9camino protecting groupxe2x80x9d designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially preferred are those amino protecting groups which are cleavable under mildly acidic conditions from about pH 2.0 to 3. Particularly preferred amino protecting groups are t-butoxycarbonyl (BOC), carbobenzyloxy (CBZ), and 9-fluorenylmethoxycarbonyl (FMOC).
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
The compound of formula I can be prepared starting from the compound of formula V by the following Reaction Scheme: 
wherein R1, R2 and R3 are as above and R4 is lower alkyl, lower alkenyl, halo lower alkyl, hydroxy lower alkyl, or xe2x80x94CH2)nxe2x80x94COOR5 and R5 is hydrogen or lower alkyl,
In the compounds of formula V wherein one of R1 and R2 is nitro, amino, chloro, bromo, or iodo and the other is hydrogen, the corresponding carboxylic acids or their lower alkyl esters are commercially available. In cases where only the carboxylic acids are available, they can be converted to the corresponding esters of lower alkyl alcohols using any conventional esterification methods. All the reactions hereto forward are to be carried out on lower alkyl esters of the compounds of formula V. The amino substituted compounds of formula V can be diazotized to yield the corresponding diazonium compound, which in situ can be reacted with the desired lower alkyl thiol, perfluoro-lower alkyl thiol (see for example, Baleja, J. D. Synth. Comm. 1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem. Soc, Chem. Comm. 1980, 756; Kau, D.; Krushniski, J. H.; Robertson, D. W, J. Labelled Compd Rad. 1985, 22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull Chem Soc. Jpn. 1980, 53, 2023; Baker, B. R.; et al, J. Org. Chem. 1952, 17, 164), or alkaline earth metal cyanide, to yield corresponding compounds of formula V, where one of the substituents is lower alkyl thio, perfluoro-lower alkyl thio, or cyano, and the other is hydrogen. If desired, the lower alkyl thio or perfluoro-lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl substituted compounds of formula V. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion.
If it is desired to produce compounds of lower alkyl or perfluoro-lower alkyl groups of compounds of formula V, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl group (see for example, Katayama, T.; Umeno, M., Chem. Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; Novak, J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S.; Tamboroski, C., J. Org Chem. 1984, 49, 478; Chen, Q, -Y.; Duan, J. -X. J. Chem. Soc. Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett. 1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No. 5,113,013) can be utilized to effect this conversion.
In the compounds of formula V wherein both of R1 and R2 are chloro or fluoro, the corresponding carboxylic acids or their lower alkyl esters are commercially available. In cases where only the carboxylic acids are available, they can converted to the corresponding esters of lower alkyl alcohols using any conventional esterification method. To produce the compound of formula V where both R1 and R2 are nitro, 3,4-dinitrotoluene can be used as starting material. This can be converted to the corresponding 3,4-dinitrophenyl acetic acid. Any conventional method of converting an aryl methyl group to the corresponding aryl acetic acid can be utilized to effect this conversion (see for example, Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M, Synthesis, 1991, 871).
The compounds of formula V where both R1 and R2 substituents are amino can be obtained from the corresponding dinitro compound of formula V, described above. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. The compound of formula V where both R1 and R2 are amine groups can be used to prepare the corresponding compound of formula V where both R1 and R2 are iodine or bromo via the diazotization reaction described before. Any conventional method of converting amino group to an iodo or bromo group (see for example , Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol, II 1943, 351) can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where both R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio groups, the compound of formula V where R1 and R2 are amino can be used as starting material. Any conventional method of converting aryl amino group to aryl thioalkyl group can be utilized to effect this conversion. If it is desired to produce compounds of formula V where R1 and R2 are lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, the corresponding compounds of formula V where R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio can be used as starting material. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where both R1 and R2 are substituted with lower alkyl or perfluoro-lower alkyl groups, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl group can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where one or both of R1 and R2 are substituted with sulfonamido, the corresponding compounds where one or both of R1 and R2 are substituted with nitro can be used as starting materials. Any standard method of converting a nitrophenyl compound to the corresponding sulfonamidophenyl compound can be used to effect this conversion.
The carboxylic acids corresponding to the compounds of formula V where one of R1 and R2 is nitro and the other is halo (for example chloro) are known from the literature (see for 4-chloro-3-nitrophenyl acetic acid, Tadayuki, S.; Hiroki, M.; Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504, Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid, Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org. Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. Tetrahedron Lett. 1995, 36, 1279). These carboxylic acids can be converted to the corresponding lower alkyl esters using any conventional esterification methods. Thus, if it is desired to produce the compound of formula V where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is nitro and the other is chloro can be used as starting material. In this reaction, any conventional method of nucleophilic displacement of aromatic chlorine group with a lower alkyl thiol can be used (see for example, Singh, P.; Batra, M. S.; Singh, H, J. Chem. Res. -S 1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem. Lett, 1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.; Yamada, A, Synthesis, 1993, 194; Sutter, M.; Kunz, W. U.S. Pat. No.; U.S. Pat. No. 5,169,951). Once the compounds of formula V where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio are available, they can be converted to the corresponding compounds of formula V where one of R1 and R2 is nitro and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl using conventional oxidation procedures.
If it is desired to produce compounds of formula V where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of reducing an aromatic nitro group to an amine can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing aromatic amino group and reacting it in situ with the desired lower alkyl thiol can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R1 and R2 is lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio, can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether group to the corresponding sulfone group can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R1 and R2 is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compounds where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing an aromatic amino group and conversion of it in situ to an aromatic halide can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of R1 and R2 is halo and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R1 and R2 is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether to the corresponding sulfone can be utilized to effect this conversion. If it is desired to produce compounds of various combinations of lower alkyl and perfluoro-lower alkyl groups of compounds of formula V, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl group can be utilized to effect this conversion.
If one wishes to prepare the compound formula V where one of R1 and R2 is nitro and the other is amino, the compound of formula V where one of R1 and R2 is nitro and other is chloro can be used as a starting material. The chloro substituent on the phenyl ring can be converted to an iodo substituent (see for example, Bunnett, J. F.; Conner, R. M.; Org Synth. Coll Vol V, 1973, 478; Clark, J. H.; Jones, C. W. J. Chem. Soc. Chem. Commun. 1987, 1409), which in turn can be reacted with an azide transferring agent to form the corresponding azide (see for example, Suzuki, H.; Miyoshi, K.; Shinoda, M. Bull. Chem. Soc. Jpn, 1980, 53, 1765). This azide can then be reduced in a conventional manner to form the amine substituent by reducing it with commonly used reducing agent for converting azides to amines (see for example, Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis, 1987, 48).
In order to prepare the compound of formula V where one of R1 and R2 is cyano and the other is amino, the compound of formula V where one of R1 and R2 is nitro and other is amino can be used as a starting material. The amino group is converted to cyano by conventional means of converting aryl-amino to aryl-cyano, for example by diazotization with a cyanide-transferring agent such as cuprous cyanide. The nitro group is converted to an amino group as described above.
If it is desired to convert commercially available compounds to compounds of formula V where one of R1 and R2 is cyano and the other is any other desired substituent, the compound of formula V where one of R1 and R2 is nitro and the other is halo is used as starting material. With this starting material, the nitro is converted to the cyano and the halo is converted to the desired R1 and R2 substituent. If it is desired to produce the compound of formula V where both R1 and R2 are cyano, this can be prepared as described hereinbefore from compounds where R1 and R2 are amino via diazotization and reaction with a cyanide-transferring agent such as cuprous cyanide.
In the first step of this Reaction Scheme, the alkyl halide of formula VI is reacted with the compound of formula V, to produce the compound of formula VII. In this reaction, if in the compounds of formula V, R1 or R2 is an amino group, such amino group(s) have to be protected before carrying out the alkylation reaction with the alkyl halide of formula VI. The amino group can be protected with any conventional acid removable group (see for example, for t-butyloxycarbonyl group see, Bodanszky, M. Principles of Peptide Chemistry, Springerxe2x80x94Verlag, New York, 1984, p 99). The protecting group has to be removed from the amino groups after preparing the corresponding amine protected compounds of formula I-axe2x80x2, I-axe2x80x3, and I-axe2x80x2xe2x80x3 to obtain the corresponding amines. The compound of formula V is an organic acid having an alpha carbon atom and the compound of formula VI is an alkyl halide so that alkylation occurs at the alpha carbon atom of this carboxylic acid. This reaction is carried out by any conventional means of alkylation of the alpha carbon atom of a lower alkyl ester of a carboxylic acid. Generally, in these alkylation reactions any alkyl halide is reacted with the anion generated from any acetic acid ester. The anion can be generated by using a strong organic base such as lithium diisopropylamide, n-butyl lithium as well as other organic lithium bases. In carrying out this reaction low boiling ether solvents are utilized such as tetrahydrofuran at low temperatures from xe2x88x9280xc2x0 C. to about xe2x88x9210xc2x0 C. being preferred. However any temperature from xe2x88x9280xc2x0 C. to room temperature can be used.
The compound of formula VII can be converted to the compound of formula XII by any conventional procedure to convert a carboxylic acid ester to an acid. The carboxylic acid of the formula XII can be converted to the amide of the formula IX. This reaction is carried out by using conventional means for converting the acid of formula XII to an acid chloride and thereafter treating this acid chloride with ammonia or an ammonia-producing compound such as hexamethyl disilazane. Conditions which are conventional for converting an acid to an acid chloride can be utilized in this procedure. This acid chloride when reacted under conventional conditions with ammonia as described will produce the amide of formula IX. The compound of formula IX when reacted with an alkyl, alkenyl, or xe2x80x94CH2)nC(O)2R5 isocyanate of formula X forms the urea adduct of formula I-axe2x80x2. Any conventional method of reacting alkyl, alkenyl, or xe2x80x94(CH2)nC(O)2R5 isocyanate with an amide to form a urea linkage can be utilized to form the compound of formula I-axe2x80x2.
When R4, is a lower alkenyl group in the compound of formula Iaxe2x80x2, this compound can be converted to the corresponding hydroxy lower alkyl group by conventional hydroboration at the olefinic group to produce a corresponding hydroxy group. The hydroxy group, if desired, can be converted to a halo group. Any method of halogenating a hydroxy group can be used in accordance with this invention.
On the other hand, if it is desired to produce the compound of formula Iaxe2x80x3 the compound of formula XII is first converted to the methyl ester of formula XI, thereafter reacting it with urea to produce the compound of formula I-axe2x80x2. This reaction is carried out by utilizing any conventional means of reacting a methyl ester with urea to form the corresponding condensation product.
The compound of formula I where R4 is CO(CH2)nCOOR6 is produced from the monoacid chloride XIII of the monoester of the corresponding dicarboxylic acid. The monoacid chloride XIII is coupled with the compounds of formula Iaxe2x80x3 using standard coupling methods.
The compound of formula VII has an asymmetric carbon atom through which the group CH2R3 and the acid amide substituents are connected. In accordance with this invention, the preferred stereoconfiguration of this group is R.
If it is desired to produce the R or the S isomer of the compound of formula I, this compound can be separated into these isomers by any conventional chemical means. Among the preferred chemical means is to react the compound of formula XII with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula XII is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula XII. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula XII in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids, i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula XII which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomer of formula I. The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula XII (see for example, Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The preferred method of resolution of racemates of the compounds of the formula XII is via the formation of corresponding diastereomeric esters or amnides. These diastereomerie esters or amnides can be prepared by coupling the carboxylic acids of the formula XII with a chiral alcohol, or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula XII can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using any conventional method to hydrolyze an ester or an amide without racemization.
The following compounds were found to have in vivo activity when administered orally in accordance with the assay described in Example B:
1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl-3-ethyl-urea;
1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea;
1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-methyl urea;
1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea;
1-Allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea;
1-[2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea;
1-[2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea;
1-[2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]3-methyl-urea
All of the compounds described in the following syntheses activated glucokinase in vitro in accordance with the assay described in Example A.